Under low oxygen availability the transcription is upregulated by the transcription factor complex HIF-1 (hypoxia-inducible factor - 1). HIF-1 is composed of two subunits HIF-1 alpha and beta. The stabilization of the alpha subunit is O2-dependent regulated by HIF-prolyl-hydroxylases (PHDs). Under normoxia PHDs modify HIF-1alpha, which is sent to proteasomal degradation.

In this study, we investigated the role of nitric oxide (NO) in regulating PHD activity and expression and the consequences thereof for HIF-1alpha degradation. We report a biphasic response of HIF-1alpha and PHDs towards NO treatment under normoxia. In the early phase NO inhibits PHD activity which leads to HIF-1alpha accumulation whereas in the late phase increased PHD activity reduced HIF-1alapha again. Enhanced PHD activity was correlated with induced expression of PHD2 and 3 at the mRNA and protein level. Induction of PHDs was strictly HIF-1alpha dependent as analysed by reportergene assays and knock out experiments. Suppression of PHDs using siRNA revealed that PHD2 was responsible for regulating HIF-1alpha degradation under NO treatment. The data suggest a role for PHD2 as oxygen sensor controlling HIF-1alpha levels under NO.